Lüdtke A, Oestereich L, Ruibal P, et al.
Ebola virus disease in mice transplanted with human hematopoietic stem cells.
J Virol.
2015 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/25673711

The current Ebola outbreak that started in March of last year in West Africa has caught the attention of the world. The deaths attributed to this disease during the last year have now surpassed all of the other known Ebola outbreaks combined. As of March 4, 2015, the World Health Organization (WHO) has reported 23,934 total confirmed cases of Ebola, with 9,792 cumulative deaths. In the three hardest hit countries; Guinea, Liberia, and Sierra Leone, 491 of these deaths were health workers caring for sick patients.

While Africa has undoubtedly been the most affected, Ebola is no longer a disease with borders, as the Centers for Disease Control and Prevention (CDC) confirmed the first laboratory-verified case of Ebola in the United States on September 30, 2014, in a man who traveled to Dallas, Texas, from Liberia. He died on October 8, 2014, and subsequently, two health-care workers at Texas Presbyterian Hospital tested positive for Ebola. A fourth case, in a physician who had served with Doctors Without Borders, was confirmed in New York City. Though he diligently tracked his exposure risk this physician still was infected by the virus. His personal account of his experience is worth reading.1 

Several therapies to treat or prevent Ebola are under development, though none have passed phase I development.2  Largely, our ability to develop and test novel therapies for subsequent clinical trials is based on small animal models of disease. Advances in Ebola research have been slowed by the lack of an appropriate small animal model, leaving only animal models such as non-human primates (NHP) that are considerably more expensive, lack the plethora of tools and reagents that we can use with rodents, and are often mired with ethical concerns. To infect mice with Ebola, researchers have used a mouse-adapted strain of Ebola Zaire, which was formed by infecting newborn mice with Ebola and serially passaging the virus in progressively older suckling mice, eventually obtaining a plaque-purified virus that was lethal for adult mice.3 However, while the adult mice can be infected, they die very quickly and don’t demonstrate the classic symptoms of disease that are exhibited in human infection.

Last October, a report in Science4  out of the Katze lab from the University of Washington was able to recapitulate many of the human disease symptoms, by infecting a genetically diverse strain of mice from the Collaborative Cross mouse,5  which was generated from founders from five classical inbred strains. While traditional laboratory mice represent approximately 15 percent of the genetic variability in mice, the Collaborative Cross strains capture roughly 90 percent of the common genetic variation amongst the three subspecies of mice. Using these genetically diverse mice resulted in some infected animals with symptoms, such as hemorrhagic disease or fatal hepatitis, similar to what is observed in man. However, this model was still only possible with mouse-adapted virus and not with the actual human strain.

A new report published in the Journal of Virology from Dr. Anja Lüdtke and colleagues from the Heinrich Pette Institute, Leibniz Institute for Experimental Virology in Germany, describes a mouse model now capable of being infected with the human variant of Ebola Zaire. To accomplish this model, the research team took advantage of an immunodeficient mouse strain, NSG, and irradiated and subsequently transplanted these mice with human CD34+ cells. After eight to 12 weeks post-transplantation, these mice then had a functioning human hematopoietic system with fully differentiated human lymphocytes and myeloid cells. Depending on the individual transplantation, mice varied in their degree of human chimerism, and were separated into a “low” engraftment group (20% to 40% human chimerism) and a “high” engraftment group (>40% human chimerism). These groups of mice were infected with the human Ebola Zaire virus, resulting in death in 75 percent of the low group and 100 percent of the high group by day 20 post-infection. As is observed in human disease, both groups of infected mice had high viremia, with blood viral titers of up to 105 focus-forming units (FFU)/mL at the peak of disease. Intriguingly, necropsies of infected mice showed liver steatosis, and in one animal, the authors observed areas of focal hemorrhage and necrosis in the liver. Splenomegaly was also seen in the Ebola-infected mice, along with considerable lymphocyte infiltrates in the spleen and lipid droplet deposits in the liver.

In Brief

This demonstration of a humanized mouse capable of being infected with human Ebola Zaire represents the first small animal model of the disease that reproduces the typical features of Ebola infection in humans, including viremia, cell damage, liver steatosis, signs of hemorrhage, and lethality. This study adds to the growing list of humanized mouse models to study infections,6,7  including the humanized BLT (bone marrow, liver, and thymus) mouse now used for HIV research, that will help to reduce the amount of expensive and limited NHP research typically used in these fields. Given the presence of a human immune system capable of being infected with the human virus, this new mouse model of Ebola disease may serve as a viable research tool for preclinical development of novel antivirals and vaccines to combat this deadly epidemic.

References

References
1.
Spencer C.
Having and fighting Ebola - Public health lessons from a clinician turned patient.
N Engl J Med.
2015;372:1089-1091.
http://www.ncbi.nlm.nih.gov/pubmed/25714039
2.
Choi WY, Hong KJ, Hong JE, et al.
Progress of vaccine and drug development for Ebola preparedness.
Clin Exp Vaccine Res.
2015;4:11-16.
http://www.ncbi.nlm.nih.gov/pubmed/25648233
3.
Bray M, Davis K, Geisbert T, et al.
A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever.
J Infect Dis.
1998;178:651-661.
http://www.ncbi.nlm.nih.gov/pubmed/9728532
4.
Rasmussen AL, Okumura A, Ferris MT, et al.
Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance.
Science.
2014;346:987-991.
http://www.ncbi.nlm.nih.gov/pubmed/25359852
5.
Collaborative Cross Consortium et al.
The genome architecture of the Collaborative Cross mouse genetic reference population.
Genetics.
2012;190:389-401.
http://www.ncbi.nlm.nih.gov/pubmed/22345608
6.
Gaska JM, Ploss A.
Study of viral pathogenesis in humanized mice.
Curr Opin Virol.
2015;11C:14-20.
http://www.ncbi.nlm.nih.gov/pubmed/25618248
7.
Brehm MA, Wiles MV, Greiner DL, et al.
Generation of improved humanized mouse models for human infectious diseases.
J Immunol Methods.
2014;410:3-17.
http://www.ncbi.nlm.nih.gov/pubmed/24607601

Competing Interests

Dr. Hoggatt indicated no relevant conflicts of interest.